Samples and data are analyzed from a longitudinal population study (1965 to 2007) that allows study of the risk factors and effects of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on development of vascular complications and mortality. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Findings on risk factors for diabetes are applied to a multicenter randomized clinical trial of prevention of type 2 diabetes that is currently in a long-term outcomes phase (the Diabetes Prevention Program Outcomes Study). Studies of the genetics of type 2 diabetes, obesity, and diabetes complications are described in other projects. Knowledge of diabetes risk factors coming from this and other studies led to the hypothesis that type 2 diabetes could be prevented or delayed in adults at high short-term risk. This hypothesis was confirmed in the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial in which many of the participants and investigators in this project participated. We are now in a long-term follow-up phase, the Diabetes Prevention Program Outcomes Study (DPPOS), to assess long-term success with weight loss, reduction in the incidence of diabetes, and effects on diabetes complications. The DPPOS also began a genetics component to test whether genes with known or suspected effects on type 2 diabetes affected diabetes incidence in the DPP and interacted with study interventions. Following the initial phase of the DPP, all active participants could enrol in DPPOS for continued management and follow-up, and 2,766 (88%) enrolled. Given the ILS benefits in the DPP, all three groups were offered group-implemented ILS. Metformin was continued in the original metformin group, and the original ILS group was offered additional lifestyle support. During the 10-year average follow-up since randomization, the original ILS group lost, then partially regained weight. The modest weight loss with metformin was maintained throughout. Diabetes incidence rates during the DPP were 11.0/100 person-years (95% confidence interval, 95%CI=9.8-12.3), 7.8 (95%CI=6.8-8.8), and 4.8 (95%CI=4.1-5.7) in the placebo, metformin, and ILS groups. During DPPOS follow-up, rates were similar in these three groups: 5.6 (95%CI=4.8-6.5), 4.9 (95%CI=4.2-5.7) and 5.9 (95%CI=5.1-6.8), respectively. Diabetes incidence over the 10-year period was reduced by 34% (95%CI=24-42) and 18% (95%CI=7-28) in those randomized to ILS and metformin. Blood pressure and lipids were similar or lower in the ILS group despite less frequent drug treatment. During post-DPP follow-up, incidence rates in the former placebo and metformin groups fell to equal those in the former ILS group, but the cumulative incidence of diabetes remained lowest in the ILS group. Diabetes prevention or delay can persist for at least 10 years.